For as long as it has been possible to measure electrical activity in the nervous system, it has been known that the brain produces oscillatory rhythms. Some rhythms are generated during sleep, others during waking;certain patterns of oscillatory brain activity occur in all healthy people, while other patterns only occur in disease states such as epilepsy, clinical depression, or schizophrenia. Many different brain rhythms have been identified and characterized, and yet almost nothing is known about their function. We know that the brain oscillates, but we do not know why. Over the past few years, discoveries have been made that provide tantalizing new clues for answering this question, by suggesting that neural oscillations are very much like "threads" that the brain weaves together to create the "fabric" of memory and perception. In rats, one particular kind of oscillation referred to as "theta rhythm" is very predominant in the hippocampus and entorhinal cortex, brain areas that play a critical role in learning and memory. It is becoming increasingly clear that theta oscillations (in the frequency band of 4-12 Hz) are building blocks from which the hippocampus and entorhinal cortex can construct memory representations. The studies proposed here will combine neurophysiological recording experiments with computational modeling studies to investigate how the rat brain uses theta oscillations to form memories of familiar locations in space. Neurons called "place cells" and "grid cells" become active whenever a rat visits certain familiar locations, and these neurons are strongly synchronized by theta oscillations. Proposed computational modeling studies will investigate how place cells and grid cells use theta oscillations to encode spatial memories, and will seek to decipher the structure of the biological neural networks that perform this task. Proposed neurophysiology studies will attempt to show for the first time that neural oscillators in subcortical regions store memory representations using a "phase code," and will examine how the cerebral cortex interacts with subcortical oscillators to read out these memory representations. Pharmacological inactivation studies will be conducted to demonstrate how memory processing breaks down when neural oscillators are disrupted, which may help to explain the causes of memory impairment in humans who suffer from amnesic syndrome in conjunction with disorders like Alzheimer's disease, schizophrenia, depression, anxiety disorders, and post-traumatic stress. By elucidating how memories are formed from theta oscillations in spatial memory circuits, the research proposed here will provide groundbreaking new insights into the fundamental role that neural oscillations play in normal memory processes. This work may in the future make it possible to diagnose and treat brain diseases and mental disorders that currently are not well understood, but which may prove to have roots in dysfunction of the neural oscillators that provide the basic building blocks for memory and perception. PUBLIC HEALTH RELEVANCE: Degeneration of memory circuits in the hippocampus and entorhinal cortex can cause amnesia and dementia in a broad spectrum of neurodegenerative and psychiatric conditions, including Alzheimer's disease, Parkinson's disease, Lewy body dementia, chronic alcoholism, multiple sclerosis, encephalitis, posttraumatic stress disorder, dissociative amnesia, and others. There are very few effective treatments for the memory impairment, confusion, disorientation, and dissociation from reality that can accompany these conditions. Research proposed here will help to identify new therapeutic targets for treating these symptoms by demonstrating how oscillatory neural networks in the hippocampus, entorhinal cortex, and associated brain regions of rats are involved in regulating memory storage and retrieval.